P676: UPDATED RESULTS FROM THE TRIAL ITCC-054/COG-AAML1921: BOSUTINIB IN NEWLY DIAGNOSED AND RESISTANT/INTOLERANT PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA
Authors: Erica Brivio, Edoardo Pennesi, Marieke Willemse, Yilin Jiang, Vincent van der Velden, Berna Beverloo, Chad Hudson, Luke Kuttschreuter, Inge van der Sluis, Benoît Brethon, Francisco Bautista, Michael J. Burke, Nyla Heerema, Andrew Bukowinski, Stacy Cooper, Jessica Pollard, Ramamoorthy Nagasubramani, Michele Redell, Jean-Pierre Bourquin, Ray Pais, Jamie Frediani, Sandeep Batra, Nicoletta Bertorello, Jessica Boklan, Albert Kheradpour, Wade Kyono, Karey Kowalski, Benjamin Mizukawa, Donna Lancaster, Laura Murillo-Sanjuán, Julie Krystal, Yves Bertrand, Alwin Huitema, Harm van Tinteren, Franco Locatelli, Michael Roth, Nobuko Hijiya, Michel Zwaan
Journal: HemaSphere (2023)

Background: Bosutinib is a second-generation Tyrosine Kinase Inhibitor (TKI), approved for adults with Chronic Myeloid Leukemia (CML), and tested for the first time in children in this phase I/II trial, sponsored by Erasmus Medical Center and the Children’s Oncology Group, and funded by Pfizer Inc. The phase I arm established the recommended phase 2 dose (RP2D) in resistant/intolerant (R/I) pediatric patients at 400 mg/m2 QD (max 600 mg/day), based on safety and target exposure as defined in adults. Extrapolation from safety and PK data in R/I children and target exposure from adults established the RP2D for newly diagnosed (ND) patients at 300 mg/m2 QD (max 500 mg/day). Aims: We present updated safety and efficacy results of bosutinib in R/I pediatric patients with CML treated at the RP2D in the phase I and II portion of the study, as well as efficacy data in ND patients. Methods: R/I and ND patients (as per ELN2013 criteria), aged 1-18 years with chronic phase CML, without evidence for organ toxicities, were enrolled. Main exclusion criteria included known T315I or V299L BCR-ABL1 mutations, use of proton pump inhibitors and CYP3A inducers/inhibitors. Due to the rarity of CML in children, the sample size was not based on formal calculations: a total of 60 patients needed to be enrolled in this phase I/II combined study per regulatory authorities’ requirements. Results: Thirteen R/I patients received the RP2D of which 11 were in phase I. Median age was 15 (range: 6-17) years, sex M:F ratio 8:5. Twelve patients were resistant and 1 intolerant to prior therapy with 5 patients having received ≥2 previous TKIs. Seven were reported in Complete Cytogenetic Response (CCyR) at baseline including 2 with Major Molecular Response (MMR). Ten patients received the capped dose of 600 mg/day. Median follow-up was 11 (range 1-25) months. At the RP2D, one patient experienced a DLT in phase I (transaminase and bilirubin increase and rash). Gastrointestinal (GI) and skin toxicities were the most common; namely 12/13 (92%) with diarrhea, of which 2 (17%) were grade 3/4, and 8/13 (62%) with skin rash, of which 1 (13%) was grade 3/4. At time of dataset lock (February 14, 2023), 11/13 (84.6%) R/I patients achieved/maintained CCyR, and 7/13 (53.8%) MMR, as best response. One patient who achieved CCyR on treatment lost the response after 12 months, while all patients which entered the study with either CCyR or MMR maintained the response. Of the 5 patients not in CCyR at baseline, 4 (80%, 95%CI: 28-99%) achieved CCyR and 1 had no response data available (on treatment for <1 month). Of the 10 patients not in MMR at baseline, 5 (50%, 95%CI: 19-81%) achieved MMR on study (2 had no response data available, on treatment for <3 months). Median time to response was 3 months for CCyR and 8 months for MMR. Two patients permanently discontinued the drug due to toxicities (one rash, one persistent GI toxicity and fatigue), three due to insufficient response. In phase II, 24 ND patients were enrolled: sex M:F ratio 15:9, median age 13 (range: 5-17) years. The median follow-up was 14 (range: 0.9-31) months. Cumulative incidence of CCyR was 77% (47%-91%) and 88.3% (95%CI 55%-98%) at 6 and 12 months respectively, and for MMR it was 23% (95%CI 7%-46%) and 30% (95%CI 10%-54%). Three patients permanently discontinued bosutinib due to intolerance four due to unsatisfactory response with 17 still on treatment at time of dataset lock. Summary/Conclusion: Bosutinib at the RP2D was well-tolerated and its preliminary efficacy in R/I and ND pediatric patients seems comparable to that recorded in adult patients treated with the same drug and in line with other second generation TKIs. Keywords: Pediatric, Chronic myeloid leukemia, Clinical trial